Mice carrying the Os mutation have a 50% decrease in nephron number. We found that ROP/Os mice had severe and diffuse glomerulosclerosis (GS), whereas C57 Os/+ mice had only minimal lesions at 5 months. These data led to the conclusion that the ROP strain is sclerosis prone, whereas C57 mice are resistant to glomerulosclerosis. We induced diabetes in 12 week old C57 Os/+ and ROP Os/+ mice with repeated injections of STZ to obtain a sustained glycemia in the range of 300-400 mg/dl. The mice were maintained for 12 weeks withour insulin treatment. The glycemia levels were adjusted initiallly so that theywould be identical in both strains. At sacrifice the renal lesions were massive in the ROP Os/+ , with diffuse and severe Kimmelstiel-Wilson nodules, and major tubulointerstitial and arteriolar lesions. In contrast, the C57 Ox/+ mice had only moderate mesangial sclerosis, and there were no tubular or vascular abnormalities. The glomerular volume of ROP Os/+ mice was larger than C57 Os/+ mice (1.37 +/-0.3x10/6 microm3 vs 0.94+/- 0.16x10/6 microm3) and the mRNAs levels for tenascin, laminin, and type IV collagen were significantly higher in ROP/OS than C57/OS mice. In conclusion these data suggest that the major determinant in the severity of diabetic nephropathy is the susceptibility to sclerosis rather than the level of glycemia.